Release Of Secretin Research Articles

Role of bile acids in the control of pancreatic secretion and CCK release

In most species stimulated pancreatic enzyme secretion and CCK release are increased in the absence and inhibited in the presence of luminal bile acids. Changes in CCK release are almost unequivocal in all investigated species. With respect to enzyme secretion, physiological bile acid concentrations seem to be necessary to exert an inhibitory effect on stimulated enzyme output in humans. Bile acids administered in higher concentrations may enhance basal and stimulated pancreatic secretion. Furthermore, the chemical properties of different bile acids (i.e., hydroxylation, conjugation) seem to contribute to their stimulating effect on enzyme secretion as was observed in several species. The rank order of bile acids inhibiting stimulated enzyme secretion in humans is taurocholate greater than taurodeoxycholate greater than taurochenodeoxycholate. On the other hand, chenodeoxycholic acid exerts the strongest stimulating effect on secretion release, which may account for the stimulating effect of this bile acid on exocrine pancreatic secretion. The strongest candidate for the mediator role in bile-acid-induced changes of exocrine pancreatic secretion is CCK (at least in dogs and rats). The CCK cell may be influenced either directly or indirectly. In conclusion, bile acids modulate pancreatic enzyme secretion and CCK release. CCK is a major candidate for this regulatory role under physiological conditions.

Beneficial effects of the synthetic trypsin inhibitor camostate in cerulein-induced acute pancreatitis in rats

The therapeutic effect and the mechanism of action of the synthetic trypsin inhibitor camostate were studied in a rat model of acute interstitial pancreatitis induced by four subcutaneous injections of 20 micrograms/kg body weight of cerulein at hourly intervals. Rats with acute pancreatitis were given either 100 mg/kg body weight camostate or volume- and pH-adjusted water via an orogastric tube 30 min after the last cerulein injection. The elevation of serum amylase activity was significantly reduced by camostate treatment and the peak value was seen 1 hr earlier than that observed in the rats that did not receive camostate. Camostate also inhibited the reduction in pancreatic content of lipase and amylase seen during experimental pancreatitis. These effects were accompanied by alleviation of the histologic signs of acute pancreatitis such as cellular infiltration and acinar cell vacuolization. After oral administration, camostate and its metabolite were absorbed from the intestine and were detectable in plasma for more than 6 hr in concentrations high enough to have antiprotease activity. In addition, camostate in the duodenum was able to increase pancreatic juice flow and protein output and to stimulate endogenous secretin release. These results suggest that oral administration of camostate reduces the severity of cerulein-induced acute pancreatitis by releasing endogenous secretin and by its antiprotease activity.

Effect of intraduodenal oligopeptide on rat pancreatic exocrine secretion and release of secretin and CCK

Effect of intraduodenal oligopeptide on rat pancreatic exocrine secretion and release of secretin and CCK

Effect of Fatty Acid on Secretin Release and Cholinergic Dependence of Pancreatic Secretion in Rats

We investigated the effects of oleic acid in the duodenum on pancreatic exocrine secretion and plasma secretin, and determined the role of cholinergic dependence on pancreatic secretion and secretin release in response to oleic acid in anesthetized rats. Oleic acid emulsion (pH 6.5) in three different doses of 0.06, 0.25, and 1 mmol/h was infused intraduodenally for 1 h with or without intravenous administration of atropine in a dose of 100 micrograms/kg/h. Intraduodenal administration of oleic acid resulted in significant increases in pancreatic juice volume and bicarbonate output, in a dose-related manner (p less than 0.001). Plasma secretin concentration caused dose-dependent elevation (p less than 0.001) by oleic acid, which correlated very well with bicarbonate output in response to oleic acid (p less than 0.001). Atropine inhibited pancreatic secretion including juice volume and bicarbonate output stimulated by oleic acid in each dose, statistically significantly (p less than 0.05-0.01), but did not affect plasma secretin concentration. Thus, we conclude that oleic acid in the duodenum stimulates pancreatic secretion and endogenous secretin release in rats, and that secretin release is not influenced by the cholinergic tone, although pancreatic secretory response is inhibited significantly.

Effect of Plaunotol on Release of Plasma Secretin and Pancreatic Exocrine Secretion in Humans

Plaunotol, an acyclic diterpene alcohol is a new antiulcer agent derived from the leaves of the plau-noi plant. We investigated the effect of plaunotol on the release of endogenous secretin with radioimmunoassay and exocrine pancreatic secretion, using a dye dilution technique with polyethylene glycol 4,000 as a nonabsorbable marker in eight human volunteers. Intrajejunal administration of plaunotol (pH 6.5) in three different doses (80, 160, and 320 mg/30 min) resulted in significant increases in both plasma secretin concentration and pancreatic bicarbonate secretion in a dose-related manner (r = 0.819 and 0.701, p less than 0.001, respectively). Bicarbonate outputs produced by plaunotol correlated well with plasma secretin concentrations (r = 0.727, p less than 0.001). Amylase output was also increased significantly by plaunotol. However, the response was not dose-dependent from that of bicarbonate output. These results indicate that endogenous secretin is released by plaunotol in humans and suggest that the increased pancreatic bicarbonate secretion can be attributed to the increased plasma secretin concentration.

Plasma Gastrointestinal Hormones during Spontaneous and Induced Menstrual Cycles*

Plasma levels of secretin, vasoactive intestinal polypeptide (VIP), somatostatin (SRIH), motilin, and/or pancreatic polypeptide, as well as serum estradiol, progesterone, PRL, LH, FSH, and/or GH were measured during the follicular phase, midcycle, and luteal phase of a spontaneous menstrual cycle in eight women and during ovarian stimulation with clomiphene citrate/human menopausal gonadotropin and hCG for in vitro fertilization in nine women. Plasma SRIH concentrations were significantly (P less than 0.02) higher in the luteal phase of spontaneous menstrual cycles than in follicular phase and midcycle. Serum GH levels, however, did not change. Plasma motilin concentrations also were higher in the luteal phase than at mid-cycle (P less than 0.04). Plasma secretin, VIP, and pancreatic polypeptide concentrations did not change during the cycle. Throughout the spontaneous menstrual cycle we found significant positive correlations between plasma SRIH and serum progesterone (P less than 0.007; r = 0.5869), plasma motilin and serum progesterone (P less than 0.02; r = 0.5331), plasma secretin and serum estradiol (P less than 0.04; r = 0.4711), and plasma secretin and serum PRL (P less than 0.02; r = 0.5507). During ovarian stimulation both plasma secretin and VIP gradually increased to a peak on cycle days 0 and 1, respectively (day 0 = the day of hCG injection), whereas plasma SRIH did not change. Serum estradiol and PRL increased significantly, and both peaked on cycle day 1. During ovarian stimulation plasma secretin correlated significantly with serum estradiol (P less than 0.00001; r = 0.9333), serum PRL (P less than 0.03; r = 0.6521), and plasma VIP (P less than 0.03; r = 0.6534). In addition, plasma VIP and serum PRL both correlated significantly with serum estradiol (P less than 0.05; r = 0.6024 and P less than 0.04; r = 0.6384, respectively). These results indicate 1) a possible effect of progesterone on the release of SRIH and motilin during the spontaneous menstrual cycle; 2) the unaltered serum GH concentrations in the luteal phase of the spontaneous menstrual cycle despite elevated plasma SRIH levels are probably due to a stimulatory effect of both progesterone and motilin on GH release; and 3) the increase in plasma secretin and VIP concentrations during ovarian stimulation is probably secondary to the concomitant increase in serum estradiol and/or PRL. We suggest that estradiol and/or PRL beyond a certain threshold level stimulate the release of secretin, and possibly also VIP, into plasma.

Plasma secretin, CCK, and pancreatic secretion in response to dietary fat in the rat.

The role of fat in regulation of pancreatic secretion was studied in conscious rats by measuring pancreatic secretion and plasma cholecystokinin (CCK) and secretin responses to intraluminal infusion of fat, protein, or trypsin inhibitor via the duodenum. In rats with pancreatic juice continuously returned to the intestine, intraduodenal infusion of 20% emulsified fat (Liposyn), 10% casein, and 0.4% ovomucoid trypsin inhibitor (OMTI) stimulated equivalent increases of approximately threefold in pancreatic protein output. Proglumide reduced fat-stimulated pancreatic protein secretion by greater than 90% but did not inhibit the response to OMTI. Fat significantly increased plasma CCK from basal levels of 0.5 pM to 2-3 pM, but it was a weaker stimulant of CCK secretion than casein (peak CCK levels greater than 10 pM) or OMTI (peak CCK levels 5-6 pM). Fat significantly stimulated secretin release (21.7 pM) compared with casein (6.8 pM), OMTI (4.4 pM), and NaCl (3.5 pM). The inhibition of fat-stimulated pancreatic secretion by proglumide indicates that the small amounts of CCK released by fat are necessary for a normal pancreatic response, suggesting that this response may be the result of potentiation between secretin and small amounts of CCK.

Regulation of Pancreatic Enzyme Secretion in Conscious Rats by Intraluminal Somatostatin: Mechanism of Action*

These studies were undertaken to characterize 1) the immunoreactive somatostatin (SS) forms found in the gastrointestinal lumen and 2) to assess the possible role of luminal SS on pancreatic exocrine function. Results indicate that different forms of SS are secreted into the rat gastric and duodenal lumen in proportions corresponding to their gastric and duodenal contents. Inhibition of diversion-stimulated pancreatic exocrine secretion by intraduodenal infusion of SS (SS-ID) is dose dependent with a maximal effective dose of 24 micrograms/kg-1h-1 for volume and 48 micrograms/kg-1h-1 for protein output. Infusion of supramaximal doses result in a loss of the inhibitory effect of SS-ID on both volume and protein outputs. Comparison between inhibition of pancreatic secretion by iv SS (SS-IV) and SS-ID indicates that SS-ID is about 20 times less potent than SS-IV in its inhibition of stimulated pancreatic exocrine secretion. Intraileal (SS-IL) infusion of SS at 48 micrograms/kg-1h-1 did not inhibit stimulated pancreatic secretion but was rather stimulatory possibly through the inhibition of putative ileal inhibitors. Likewise, passive immunization against circulating SS did not affect the inhibitory effects of SS-ID on pancreatic secretion. These data indicate that SS is secreted into the rat gastrointestinal lumen and that its infusion into the duodenal lumen inhibits stimulated pancreatic secretion in a dose-dependent fashion. The observation that SS-IL did not inhibit pancreatic secretion and that passive immunization against circulating SS did not affect the inhibitory effect of SS-ID suggest that the action of SS-ID on stimulated exocrine pancreatic secretion is probably indirect and may involve a duodenal signal, possibly an inhibition of endogenous release of cholecystokinin and/or secretin.

Effect of pancreatic juice diversion on secretin release in rats

We investigated a possible role of secretin in the mechanism of exocrine pancreatic secretion after exclusion of pancreatic juice from the intestine in anesthetized rats. Diversion of pancreatic juice from the duodenum resulted in a significant increase in plasma secretin concentration from 0.76 ± 0.39 pM at 0 time to 3.09 ± 0.30 pM at 4 h after diversion. This increase in secretin coincided with a steady but significant increase in pancreatic secretion of volume and bicarbonate. Intraduodenal administration of fresh pancreatic juice completely reversed the diversion-induced increases in both plasma secretin and pancreatic secretion. Intravenous injection of a rabbit-antisecretin serum blocked the increase of pancreatic secretion during diversion of pancreatic juice from the duodenum. Thus, we conclude that endogenous secretin is involved in a hormonal mechanism regulating increased pancreatic exocrine secretion in pancreatic juice-diverted rats.

Fat and pancreatic secretion.

In 10 healthy volunteers we investigated the effects of intraduodenal oleic acid at various concentrations (0-40 mM) and at various degrees of emulsification on pancreaticobiliary secretion and the release of secretin and cholecystokinin (CCK) into plasma. We found that the release of the two hormones was directly related to the dose of fat and to the degree of emulsification. The threshold of CCK release (and amylase output) was low in comparison with the threshold for secretin release (and bicarbonate or volume output). When the degree of emulsification of the fat was increased, no simple relation was observed between hormone levels and pancreatic exocrine secretion. The output of bile salts was identical at various fat concentrations. We conclude that both secretin and CCK are dose-dependently released by emulsions of oleic acid in normal man and that the thresholds for release are probably different.

Effects of Oleic Acid and Oleyl Alcohol on Cholecystokinin and Secretin in Plasma and Pancreatobiliary Secretion

To evaluate the importance of the terminal carboxy group of the oleic acid molecule in the release of secretin and cholecystokinin (CCK) to plasma, six normal persons were stimulated twice with duodenal perfusates containing either 20 mM oleic acid or 20 mM oleyl alcohol. Oleic acid increased the pancreatic secretion of bicarbonate and amylase and the concentrations of secretin and CCK in plasma and provoked gallbladder emptying. Oleyl alcohol only increased the amylase output slightly, but significantly. It is concluded that the carboxy group of the fat molecule has an important role in triggering the release of secretin and CCK to plasma.

Plaunotol Stimulates Endogenous Secretin Release and Exocrine Pancreatic Secretion in Rats

The effect of the new antiulcer agent plaunotol on the release of endogenous secretin and the pancreatic exocrine secretion was investigated in anesthetized rats. In 48 rats with pancreatic and biliary diversion, continuous intraduodenal infusion of plaunotol in 3 graded doses (5, 20 and 80 mg/h/rat) resulted in significant increases in both circulating plasma secretin concentration and pancreatic exocrine secretion, including volume and bicarbonate output, in a dose-dependent manner (r = 0.655, p less than 0.001; r = 0.598, p less than 0.001; r = 0.436, p less than 0.01, respectively). The pancreatic bicarbonate output was closely correlated to plasma secretin concentrations (r = 0.631, p less than 0.001). Amylase output also increased after plaunotol administration, but not in a dose-dependent manner (r = 0.092, n.s.). These findings suggest strongly that the increase in pancreatic secretion of fluid and bicarbonate output was mainly due to increased endogenous secretin release resulting from plaunotol administration.

Gut hormone release by intraduodenal stimulation in duodenal ulcer patients.

After an overnight fast, plasma levels of gut peptide hormones were determined before and after intraduodenal stimulation (IDS) with glucose and citric acid in 8 patients with a recent endoscopically proved duodenal ulcer (DU) attack and in 8 healthy volunteers. The DU patients had a hyperacidic mean BAO of 6.6 and an average PAO of 41.8 mEq/h. In DU, basal secretin levels were similar to those in controls, and after IDS secretin release was not impaired. There was no defect of VIP liberation or of the neurotensin response (basal 21 +/- 7 vs 16 +/- 3, after IDS 68 +/- 28 vs 35 +/- 5 pmol/l) which could account for gastric acid hypersecretion. Although fasting GIP levels were significantly lower than in controls (16 +/- 2.5 vs 25 +/- 1.4 pmol/l), they did not correlate negatively with BAO. In contrast to former studies with oral test meals, integrated GIP release was rather reduced after IDS. Basal plasma levels of gastrin were significantly lower in DU (4.0 +/- 0.4 vs 12 +/- 2 pmol/l) and were inversely related to BAO (r = -0.82, p less than 0.02). From the present data, there is insufficient evidence for abnormal plasma levels of gut hormones as major etiologic factors for basal hyperchlorhydria in ordinary DU disease.

Acid-independent release of secretin and cholecystokinin by intraduodenal infusion of fat in humans.

In order to clarify a possible role of fat content in the release of secretin and cholecystokinin by liquid nutritional supplements in humans, duodenal pH and plasma concentrations of secretin and cholecystokinin were studied during the intraduodenal infusion of Ensure, Vivonex, 10% Intralipid, and sodium oleate. Significant release of secretin was observed with Intralipid and sodium oleate, while significant release of cholecystokinin was observed with all four testing solutions. Duodenal pH was rarely below 4.5 during the infusion of Ensure, Intralipid, and sodium oleate. Duodenal pH was high, greater than 6.0, when plasma secretin and cholecystokinin levels were elevated during the administration of Ensure, Intralipid, and sodium oleate. We conclude that both secretin and cholecystokinin are released in response to fat solutions in the duodenum and that low duodenal pH was not responsible for either secretin or cholecystokinin release during intraduodenal infusions of Ensure, Intralipid, or sodium oleate.

Release of secretin along the canine small intestine.

The profile of secretin release along the entire canine small intestine was examined in this study. Four equal loops of the small gut, from the duodenal bulb to the ileocoecal valve, were isolated. In eight anesthetized dogs the four segments were perfused for 40 min each in random order with an acidified (pH 2.5) emulsion of 20 mM oleic acid. In four dogs control experiments were performed using 0.15 M saline. Secretin release in portal venous blood was measured by a sensitive radioimmunoassay. Although secretin was mainly released in the first quarter of the small intestine (310 pM X 40 min), large amounts of secretin, 33% of the total secretin release, were liberated in the second quarter of the small intestine (164 pM X 40 min). Minute amounts of secretin (23 pM X 40 min) were released in the third quarter, whereas perfusion of the last quarter of the small gut failed to release secretin. We conclude that the major portion of secretin is releasable in the first quarter of the small gut. High amounts of secretin can be liberated in the second quarter of intestine, an area that is probably never exposed to pH below 4.5 (the known threshold for secretin release by acid), but is still exposed to fatty acids (other releasers of secretin).

To extract or not to extract in secretin radioimmunoassay?

The importance of an ethanol extraction procedure in the radioimmunoassay of plasma secretin was investigated. The extraction step led to a higher assay sensitivity of 0.35 fmol/ml, compared to 5.93 fmol/ml using unextracted samples. The rise of plasma secretin after infusion of a low dose of secretin (1 pmol.kg-1.h-1) in 10 healthy humans was only detected after sample extraction. Higher doses (3 and 9 pmol.kg-1.h-1) resulted in increments of plasma IRS (immunoreactive secretin), which could be recorded both with and without sample extraction. After a steak meal 7 of 10 subjects showed a significant increase of plasma secretin assaying extracted plasma samples. The secretin release occurred in spikes. The mean increase of plasma IRS in this group was 0.6 fmol/ml, the mean maximal secretin release above basal was 2.3 fmol/ml. Without sample extraction, plasma secretin was not significantly changed. We conclude that plasma samples should be extracted in order to detect physiological postprandial secretin release.

Pancreatic bicarbonate response to HCl before and after cutting the extrinsic nerves of the pancreas in dogs.

In two sets of dogs with gastric and pancreatic fistulas, we studied the effect of atropine on pancreatic bicarbonate output and release of secretin in response to intraduodenal HCl before and after stepwise removal of the extrinsic nerves of the pancreas, i.e., celiac and superior mesenteric ganglionectomy alone or truncal vagotomy alone and truncal vagotomy plus celiac and superior mesenteric ganglionectomy. Ganglionectomy alone did not alter the incremental bicarbonate response to HCl. Truncal vagotomy alone significantly (P less than 0.05) decreased the incremental bicarbonate response to low (1.5 and 3 mmol/h) but not high (6 to 24 mmol/h) loads of HCl. Additional ganglionectomy restored the bicarbonate response to prevagotomy levels. With the extrinsic nerves intact and after ganglionectomy, but not after truncal vagotomy and truncal vagotomy plus ganglionectomy, intravenous atropine (14 nmol.kg-1.h-1) significantly reduced the incremental bicarbonate response to low (1.5 and 3 mmol/h) but not high loads of HCl. Neither the different surgical procedures nor atropine significantly altered plasma levels of secretin basally and in response to intestinal HCl. We conclude that 1) cholinergic fibers within the vagus nerves but not the splanchnic nerves are important mediators of the pancreatic bicarbonate response to low loads of HCl and 2) release of secretin by intestinal HCl is not under cholinergic and splanchnic control.

Effect of Trypsin on the Hormonal Regulation of the Fat-Stimulated Human Exocrine Pancreas

To study the effects of trypsin on the pancreaticobiliary secretion and the release of secretin and cholecystokinin (CCK) to plasma, seven normal subjects were stimulated twice with duodenal perfusates containing 20 mM oleic acid (pH 6.0) with and without 1 g of bovine trypsin added per liter. In addition, six patients with advanced pancreatic insufficiency who received only the oleic acid were compared with eight normal subjects. The concentrations of secretin and CCK in plasma and the pancreatic enzyme and volume secretions were unaffected by the addition of trypsin, but the initial bile acid output and the bicarbonate secretion in the period after gallbladder emptying were reduced during perfusion with trypsin. The severely reduced enzyme secretion in chronic pancreatitis did not influence the basal or oleic acid-stimulated concentrations of the hormones in plasma. The study does not support the hypothesis of a trypsin-mediated negative feedback control of human pancreatic enzyme secretion. Furthermore, the reduced duodenal output of bicarbonate found in response to trypsin is not explained by changes in the release of secretin or CCK.

Peptide YY inhibits pancreatic secretion by inhibiting cholecystokinin release in the dog

Peptide YY inhibits the pancreatic exocrine secretion (bicarbonate, water, and protein) that is stimulated by cholecystokinin, secretin, or neurotensin in the dog, but whether peptide YY inhibits the release of gut peptides that stimulate pancreatic exocrine secretion is not known. Six dogs were prepared with gastric, pancreatic, and cecal cannulas. On separate days, a single dose of sodium oleate (3, 6, 7.5, 9, 12, 15, or 18 mmol/h) was given intraduodenally for 90 min, either alone (control) or in combination with peptide YY (25, 50, 100, 200, or 400 pmol/kg · h, i.v.). We measured plasma levels of cholecystokinin-33/39, secretin, neurotensin, and peptide YY by radioimmunoassay. During infusion of peptide YY, the integrated release of cholecystokinin (3.3 ± 0.5 ng-[0–90] min/ml) was decreased significantly (p < 0.05) when compared with control values (5.6 ± 0.6). Release of secretin and neurotensin was not affected. A positive correlation (p < 0.05) was found between the release of cholecystokinin and pancreatic protein output in both control (r = 0.68) and peptide YY-treated (r = 0.67) groups. Release of peptide YY was significant after intraduodenal or intracolonic administration of sodium oleate. These studies demonstrate that inhibition of pancreatic protein secretion by peptide YY in dogs is mediated, at least in part, by an inhibition of the release of cholecystokinin.

Retardation of gastric emptying of solid food by secretin

The effect of secretin at nearly physiologic plasma concentrations on the gastric emptying rate of solid food was studied in 12 healthy men. A 99mTc colloid-labeled pancake was used as the test meal. The gastric emptying rate was measured during 1 h using a dual-headed γ-camera, and was expressed as the half-time of the emptying curve. To prevent endogenous secretin release, 400 mg of cimetidine was given before the meal. Subjects were studied under three conditions: (1) during infusion of saline; (2) during continuous infusion of secretin, 6.6 pmol/ kg · h; and (3) during three intermittent 10-min periods of secretin infusion, 7.6 pmol/kg · h during each period. Both continuous and intermittent infusion of secretin increased half-emptying time, by 133% and 55%, respectively. The plasma secretin concentration in condition 1 was 0.8 pM; plateau concentration in condition 2 was 9.8 pM; and integrated mean concentration in condition 3 was 4.8 pM. It is concluded that secretin at approximately physiologic plasma concentrations retards gastric emptying of solid food in humans.